Studies on individuals and animals with genetic defects in serotonin function can shed light on the role of this neurotransmitter in behavior and on the role of milder functional variants in serotonin genes in predisposing individuals to psychopathologies and to alcoholism. We are identifying probands for family studies by measuring the serotonin metabolite 5-HIAA in cerebrospinal fluid and by identifying individuals with amino acid substitutions in genes involved with serotonin function. Two 5-HT1A variants are rare amino acid substitutions (22Gly--Ser and 28Val--Ile), one conservative and one nonconservative. The 5-HT2C variant is a common (allele frequency=0.18) nonconservative substitution (Cys--Ser). Two 5HT2A amino acid substitutions (Ile--Val and His--Tyr) have allele frequencies of 0.01 and 0.09. Rare serotonin transporter and 5-HT7 amino acid substitutions were also discovered. For association and direct gene analysis, we have collected more than 40 cell lines from each of the following populations: anorexia nervosa (collaboratively with W. Kaye), obsessive compulsive disorder (D. Murphy), low CSF 5-HIAA with Type II alcoholism (M. Linnoila, M. Virkkunen, M. Eggert), and seasonal affective disorder (N. Rosenthal, N. Ozaki). The detected polymorphisms are converted to PCR RFLPs or allele-specific amplification markers for ease of analysis. Using the CEPH reference pedigrees and the polymorphisms at these genes, each gene is genetically mapped to its chromosomal location. For direct gene analysis, we mainly use single- strand conformational polymorphism analysis and direct sequencing. A TPH polymorphism was found to be associated with low CSF 5-HIAA and suicidality in impulsive alcoholic Finns. For serotonin receptors, coding sequence polymorphisms of 5-HT1A, 5-HT1Dalpha, 5-HT1Dbeta, 5-HT2C, 5-HT2A, 5-HT1E, and 5-HT7 were identified.